Conformation-Activity Relationships

构象-活性关系

• 批准号: 7416722
• 负责人: Richard E. Taylor
• 金额: $ 27.96万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7416722
• 关键词: ATP phosphohydrolase; Affect; Alkenes; Anabolism; Anti-Bacterial Agents; Antifungal Agents; Area; Attention; Binding; Biological; Biological Assay; Biological Factors; Carbon; Class; Classification; Collaborations; Complement; Complex; Computing Methodologies; DNA Sequence Rearrangement; Development; Epothilones; Ethers; Ethyl Ether; Evolution; Fermentation; Future; Gene Cluster; Generations; Glycol; Grant; Investigation; Lactones; Lead; Macrolides; Methodology; Methods; Microtubule Polymerization; Microtubules; Minor; Mitotic; Modification; Molecular; Molecular Conformation; Mono-S; Nuclear Magnetic Resonance; Numbers; Organism; Pattern; Peripheral; Pliability; Preparation; Property; Proteins; Pyrans; Range; Reaction; Research; Research Personnel; Route; Skeleton; Solutions; Structure; Structure-Activity Relationship; Study Subject; System; Techniques; Therapeutic; analog; apoptolidin; chemotherapeutic agent; cytotoxicity; design; desire; functional group; improved; insight; interest; novel; peloruside A; pharmacophore; preference; professor; programs; spatial relationship

DESCRIPTION (provided by applicant): Our overall program is interested in the fundamental issues regarding the evolution of polyketide natural products. The focus of these studies is from two complementary perspectives. The first deals with specific structural features found in polyketides, their effect on conformation, and the importance of conformation on biological activity. The second perspective focuses on structurally related polyketides and the co-evolution of their protein targets. Polyketide natural products are ideal subjects for these studies due to their complex structure and diverse biological activities which have shown utility towards the study and treatment of a number of therapeutic areas. During the previous research period we have shown that conformation is an important complement to classic structure-activity relationships and provides useful information for the development of future chemotherapeutic agents. As a proof of principle, a conformation-activity relationship study of the microtubule-stabilizing natural products, the epothilones, provided important information with regards to the pharmacophore as well as new leads for further development. During the next grant period, our studies will investigate three fundamentally unique projects, 1. Conformation-activity relationships of peloruside A, 2. a study of the evolutionary relationship between apoptolidin and structurally related plecomacrolides, bafilomycin and concanamycin, and 3. The development of precursor-directed biosynthetic techniques for the preparation of complex polyketide analogues. The complex natural products targeted in this application will be prepared via unique but practical synthetic strategies. Moreover, where appropriate, we have incorporated the development of a number of new synthetic methods for the preparation of complex structural units common to polyketide natural products.

描述（由申请人提供）：我们的整体项目对聚酮类天然产物进化的基本问题感兴趣。这些研究的重点是从两个互补的角度。第一部分涉及聚酮类化合物的特定结构特征，它们对构象的影响，以及构象对生物活性的重要性。第二种观点侧重于结构相关的聚酮及其蛋白靶点的共同进化。聚酮类天然产物因其复杂的结构和多样的生物活性而成为这些研究的理想对象，在许多治疗领域的研究和治疗中显示出实用性。在之前的研究中，我们已经证明了构象是经典构效关系的重要补充，并为未来化疗药物的开发提供了有用的信息。作为一种原理证明，对稳定微管的天然产物埃泊霉素的构象-活性关系的研究为药效团的研究提供了重要的信息，并为其进一步开发提供了新的线索。在下一个资助期内，我们的研究将调查三个基本独特的项目，1。紫荆苷A， 2的构象-活性关系。2 . apoptolidin与结构相关的plecomacroliides、bafilomycin和concanamycin的进化关系研究。前体导向生物合成技术在制备复杂聚酮类似物方面的发展。本应用中的复杂天然产物将通过独特但实用的合成策略制备。此外，在适当的情况下，我们还开发了一些新的合成方法，用于制备聚酮类天然产物常见的复杂结构单元。